Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Journal Club: Fidaxomicin versus Vancomycin for Clostridium Difficile Infection

15,318 views

Published on

Journal Club and Article Critique presented during an Internal Medicine Rotation at the Miami VA in June 2011.

  • DOWNLOAD THAT BOOKS INTO AVAILABLE FORMAT (2019 Update) ......................................................................................................................... ......................................................................................................................... Download Full PDF EBOOK here { https://urlzs.com/UABbn } ......................................................................................................................... Download Full EPUB Ebook here { https://urlzs.com/UABbn } ......................................................................................................................... Download Full doc Ebook here { https://urlzs.com/UABbn } ......................................................................................................................... Download PDF EBOOK here { https://urlzs.com/UABbn } ......................................................................................................................... Download EPUB Ebook here { https://urlzs.com/UABbn } ......................................................................................................................... Download doc Ebook here { https://urlzs.com/UABbn } ......................................................................................................................... ......................................................................................................................... ................................................................................................................................... eBook is an electronic version of a traditional print book that can be read by using a personal computer or by using an eBook reader. (An eBook reader can be a software application for use on a computer such as Microsoft's free Reader application, or a book-sized computer that is used solely as a reading device such as Nuvomedia's Rocket eBook.) Users can purchase an eBook on diskette or CD, but the most popular method of getting an eBook is to purchase a downloadable file of the eBook (or other reading material) from a Web site (such as Barnes and Noble) to be read from the user's computer or reading device. Generally, an eBook can be downloaded in five minutes or less ......................................................................................................................... .............. Browse by Genre Available eBooks .............................................................................................................................. Art, Biography, Business, Chick Lit, Children's, Christian, Classics, Comics, Contemporary, Cookbooks, Manga, Memoir, Music, Mystery, Non Fiction, Paranormal, Philosophy, Poetry, Psychology, Religion, Romance, Science, Science Fiction, Self Help, Suspense, Spirituality, Sports, Thriller, Travel, Young Adult, Crime, Ebooks, Fantasy, Fiction, Graphic Novels, Historical Fiction, History, Horror, Humor And Comedy, ......................................................................................................................... ......................................................................................................................... .....BEST SELLER FOR EBOOK RECOMMEND............................................................. ......................................................................................................................... Blowout: Corrupted Democracy, Rogue State Russia, and the Richest, Most Destructive Industry on Earth,-- The Ride of a Lifetime: Lessons Learned from 15 Years as CEO of the Walt Disney Company,-- Call Sign Chaos: Learning to Lead,-- StrengthsFinder 2.0,-- Stillness Is the Key,-- She Said: Breaking the Sexual Harassment Story That Helped Ignite a Movement,-- Atomic Habits: An Easy & Proven Way to Build Good Habits & Break Bad Ones,-- Everything Is Figureoutable,-- What It Takes: Lessons in the Pursuit of Excellence,-- Rich Dad Poor Dad: What the Rich Teach Their Kids About Money That the Poor and Middle Class Do Not!,-- The Total Money Makeover: Classic Edition: A Proven Plan for Financial Fitness,-- Shut Up and Listen!: Hard Business Truths that Will Help You Succeed, ......................................................................................................................... .........................................................................................................................
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • DOWNLOAD FULL BOOKS, INTO AVAILABLE FORMAT ......................................................................................................................... ......................................................................................................................... ,DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ......................................................................................................................... ......................................................................................................................... .............. Browse by Genre Available eBooks ......................................................................................................................... Art, Biography, Business, Chick Lit, Children's, Christian, Classics, Comics, Contemporary, Cookbooks, Crime, Ebooks, Fantasy, Fiction, Graphic Novels, Historical Fiction, History, Horror, Humor And Comedy, Manga, Memoir, Music, Mystery, Non Fiction, Paranormal, Philosophy, Poetry, Psychology, Religion, Romance, Science, Science Fiction, Self Help, Suspense, Spirituality, Sports, Thriller, Travel, Young Adult,
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • DOWNLOAD FULL BOOKS, INTO AVAILABLE FORMAT ......................................................................................................................... ......................................................................................................................... ,DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ,DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yyxo9sk7 } ......................................................................................................................... ......................................................................................................................... ......................................................................................................................... .............. Browse by Genre Available eBooks ......................................................................................................................... Art, Biography, Business, Chick Lit, Children's, Christian, Classics, Comics, Contemporary, Cookbooks, Crime, Ebooks, Fantasy, Fiction, Graphic Novels, Historical Fiction, History, Horror, Humor And Comedy, Manga, Memoir, Music, Mystery, Non Fiction, Paranormal, Philosophy, Poetry, Psychology, Religion, Romance, Science, Science Fiction, Self Help, Suspense, Spirituality, Sports, Thriller, Travel, Young Adult,
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • DOWNLOAD FULL BOOKS, INTO AVAILABLE FORMAT ......................................................................................................................... ......................................................................................................................... 1.DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yxufevpm } ......................................................................................................................... 1.DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yxufevpm } ......................................................................................................................... 1.DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yxufevpm } ......................................................................................................................... 1.DOWNLOAD FULL. PDF EBOOK here { https://tinyurl.com/yxufevpm } ......................................................................................................................... 1.DOWNLOAD FULL. EPUB Ebook here { https://tinyurl.com/yxufevpm } ......................................................................................................................... 1.DOWNLOAD FULL. doc Ebook here { https://tinyurl.com/yxufevpm } ......................................................................................................................... ......................................................................................................................... ......................................................................................................................... .............. Browse by Genre Available eBooks ......................................................................................................................... Art, Biography, Business, Chick Lit, Children's, Christian, Classics, Comics, Contemporary, Cookbooks, Crime, Ebooks, Fantasy, Fiction, Graphic Novels, Historical Fiction, History, Horror, Humor And Comedy, Manga, Memoir, Music, Mystery, Non Fiction, Paranormal, Philosophy, Poetry, Psychology, Religion, Romance, Science, Science Fiction, Self Help, Suspense, Spirituality, Sports, Thriller, Travel, Young Adult,
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here
  • DOWNLOAD FULL eBOOK INTO AVAILABLE FORMAT ......................................................................................................................... ......................................................................................................................... 1.DOWNLOAD FULL. PDF eBook here { https://tinyurl.com/y6a5rkg5 } ......................................................................................................................... 1.DOWNLOAD FULL. EPUB eBook here { https://tinyurl.com/y6a5rkg5 } ......................................................................................................................... 1.DOWNLOAD FULL. doc eBook here { https://tinyurl.com/y6a5rkg5 } ......................................................................................................................... 1.DOWNLOAD FULL. PDF eBook here { https://tinyurl.com/y6a5rkg5 } ......................................................................................................................... 1.DOWNLOAD FULL. EPUB eBook here { https://tinyurl.com/y6a5rkg5 } ......................................................................................................................... 1.DOWNLOAD FULL. doc eBook here { https://tinyurl.com/y6a5rkg5 } ......................................................................................................................... ......................................................................................................................... ......................................................................................................................... .............. Browse by Genre Available eBooks ......................................................................................................................... Art, Biography, Business, Chick Lit, Children's, Christian, Classics, Comics, Contemporary, CookeBOOK Crime, eeBOOK Fantasy, Fiction, Graphic Novels, Historical Fiction, History, Horror, Humor And Comedy, Manga, Memoir, Music, Mystery, Non Fiction, Paranormal, Philosophy, Poetry, Psychology, Religion, Romance, Science, Science Fiction, Self Help, Suspense, Spirituality, Sports, Thriller, Travel, Young Adult,
       Reply 
    Are you sure you want to  Yes  No
    Your message goes here

Journal Club: Fidaxomicin versus Vancomycin for Clostridium Difficile Infection

  1. 1. Fidaxomicin versusVancomycin for Clostridium Difficile Infection N Engl J Med 2011:364:422-31 Authors: Louie TJ, Miller MA, Mullane KM et. al. Joy A. Awoniyi, PharmD Candidate 2012 Florida Agricultural and Mechanical University June 20, 2011 Preceptor: Dr. Helen Yotseff, PharmD Internal Medicine Miami Veterans Affairs Medical Center
  2. 2. Background – C. Difficile Clostridium Difficile• Gram-positive, anaerobic, spore-forming bacillus• Infection is a result of a disturbance of the normal flora of the colon• Responsible for development of antibiotic- associated diarrhea and colitis• Incidence and severity of infection is increasing • Emergence of a hypervirulent strain: NAP1/B1/027 • Reduced clinical response, increased recurrence
  3. 3. Background – C. Difficile SHEA-IDSA 2010 Clinical Practice Guideline Recommendations Nature of Recommendation InfectionMild-Moderate Metronidazole 500mg orally three times daily for 10-14 days Severe Vancomycin 125mg orally four times daily for 10- 14 days Severe, Vancomycin 500mg orally or rectally 4 times daily Complicated -with or without- Metronidazole intravenously 500mg every 8 hours
  4. 4. Background - Fidaxomicin • Macrolytic Antibiotic • 8 times more active than Vancomycin in vitro against isolates of C. Difficile • Highly active, but more selective • Associated with a low rate of recurrence in a Phase 2 Trial(2009)
  5. 5. Study Objective The stated purpose of this study was to “compare the efficacy andsafety of fidaxomicin with those ofvancomycin in treating Clostridium Difficile infection”
  6. 6. Methods Study Design Research and Analysis• Double-blind • Written, informed consent provided by each patient• Randomized • Sponsored by Optimer• Parallel Group Pharmaceuticals• Multi-center • Analysis performed by the authors and one investigator at Optimer Pharmaceuticals
  7. 7. Methods Inclusion Criteria Exclusion Criteria • Life-threatening or fulminant infection• 16 years or older • Toxic megacolon• Clostridium Difficile diagnosis • Previous exposure to fidaxomicin • Diarrhea with more than 3 unformed stools within 24 hours • History of ulcerative colitis or Chron’s • Toxin A, B or both in stool disease specimen obtained 48 hours before randomization • More than one occurrence of C. Difficile infection three months before the start of the study Note: Patients may have received up to 4 doses of Metronidazole or Vancomycin in the 24 hour period prior to randomization
  8. 8. Methods Study Population• 692 patients enrolled • 596 in the modified intention-to-treat population • 548 in the per-protocol population• Centers located in the United States and Canada• Stratified according to whether infection was the first or second episode within 3 months
  9. 9. Baseline Characteristics
  10. 10. Intervention • Each subject was randomized to receive a study medication orally every 6 hours for ten days • All pills were encapsulated to look the same Fidaxomicin Group Vancomycin Group• 200mg every 12 hours • 125mg every 6 hours• Intervening doses of • No placebo placebo
  11. 11. Assessment• Patients were assessed daily for clinical cure or failure• Recurrence was recorded by a weekly assessment for 28 days after the last dose• Patient-initiated reassessment was performed if diarrhea occurred
  12. 12. Study OutcomesPrimary Endpoint• Rate of clinical cure in the modified intention- to-treat and per-protocol populationsSecondary Endpoints• Recurrence of infection during the 4-week period after the end of the course of therapy• Global cure in the modified intention to treat and per-protocol populations
  13. 13. Definitions • Resolution of diarrhea and maintenance of resolution for the duration of therapy and no further requirement •Persistence of diarrhea and need for additional therapy •Resolution of diarrhea without recurrence • Reappearance of more than 3 diarrheal stools per 24 hour period within 4 weeks after the cessation of therapy
  14. 14. Statistical AnalysisRate of Clinical Cure One-sided lower 95.7% confidence intervalRecurrence and Overall Cure Post Hoc Hypothesis Tests *Significance level of 0.05Treatment differences Post Hoc Analysis• Age• Inpatient vs. Outpatient• Prior Occurrence• Disease Severity• Strain TypeTime to Resolution of Diarrhea Kaplan-Meier MethodComparison of time to resolution Gehan-Wilcoxon Test
  15. 15. Results Primary EndpointClinical Cure• Modified Intention to Treat • 88.26% with Fidaxomicin • 85.80% with Vancomycin Lower boundary of 97.5% CI for difference of -3.1 percentage points• Per-protocol • 92.1% with Fidaxomicin • 89.8% with Vancomycin Lower boundary of 97.5% CI for difference of -2.6 percentage points
  16. 16. Results Secondary EndpointRecurrence rate was significantly lowerfor patients treated with fidaxomicin• Modified Intention to Treat (P=0.005) • 15.4% with Fidaxomicin • 25.3% with Vancomycin 95% CI, -16.6 to -2.9• Per-protocol (P=0.004) • 13.3% with Fidaxomicin • 24.0% with Vancomycin 95% CI, -17.9 to -3.3
  17. 17. Results• Rates of recurrence were similar among both groups when comparing patients infected with the resistant strain• With other strains, the rate of recurrence was lower with fidaxomicin •Results represented a 69% relative reduction in recurrences Recurrence Rates BI/NAP/027 Strain Other Strains 24.40% 23.60% 25.50% 7.80% Fidaxomicin Vancomycin
  18. 18. Results Secondary EndpointGlobal Cure – Higher rates of resolution ofdiarrhea without recurrence were seenwith fidaxomicin.• Modified Intention to Treat (P=0.006) • 74.6% with fidaxomicin • 64.1% with vancomycin 95% CI, 3.1 to 17.7• Per-protocol (P=0.006) • 77.7% with Fidaxomicin • 67.1% with Vancomycin 95% CI, 3.1 to 17.9
  19. 19. Results Notable Adverse Reactions Reported in the Safety Population Event Fidaxomicin Vancomycin P-Value (N=300) (N =323)Any Adverse Event 187 (62.3%) 10(60.4%) 0.6224 Chills 1(0.3%) 8 (2.5%) 0.0389 Dizziness 12 (4%) 4 (1.2%) 0.0405 Rash 9 (3%) 2 (0.6%) 0.0315Any Serious Adverse 75 (25%) 78 (24.1%) 0.8523 Event Laboratory 14 (4.7%) 4 (1.2%) 0.0148 Abnormalities*All Cause Mortality 16 (5.3%) 21 (6.5%) 0.6122 *Laboratory Abnormalities included hyperuricemia and increased ALT/AST but the differences between groups seemed to be of incidental, unrelated findings.
  20. 20. Author’s Conclusions• Rates of clinical cure after treatment with fidaxomicin were non-inferior to those after treatment with vancomycin• Fidaxomicin was associated with a lower rate of recurrence of C. Difficile infection associated with non-North American Pulsed Field type 1 strains
  21. 21. Article Critique
  22. 22. TitleFidaxomicin versus Vancomycin for Clostridium Difficile infection• Un-biased• Overall, reflective of the study question and study outcome• Severity of disease not mentioned, while “treatment of Clostridium Difficile” is guided by severity• “Versus” may imply superiority, which was not the objective of the study
  23. 23. Abstract• Well structured • Background • Methods • Results • Conclusions• Study endpoints were addressed in each segment, directly or indirectly
  24. 24. Introduction and Background Good Could Be Better• Addressed the current clinical • The disease state, C. Difficile relevance of the study Associated Diarrhea, is not adequately described• Referenced outcomes of a • Risk factors previous Phase II trial of • Clinical Presentation Fidaxomicin (“diarrhea” never • Links past findings to the mentioned) study objective • Emphasis on burden to facility, rather than burden to patient
  25. 25. Study Design Good Could Be Better• Appropriate time frame • Analysis of data was (5/2006 – 8/2009) performed by the authors,• Double-blinded and which included employees Randomized by computer and stock-owners for • Medication kit and number Optimer Pharmaceuticals, to each patient manufacturer of the study• Utilized both Modified drug intention-to-treat and Per protocol populations• IRB Approved
  26. 26. Study Population Good Could Be Better• Multi-centered • Possible confounding factors• Informed consent • Use of proton-pump Inhibitors/ H-2 Antagonists• Characteristics evenly distributed among • Selection Bias: Inclusion of treatment groups patients previously treated with vancomycin but not• Appropriate age group: fidaxomicin Advanced age is a risk factor • mITT mean age: 61.6 16.9 • PP mean age: 61.3 17.1
  27. 27. Intervention and Assessment Good Could Be Better• Treatment guidelines were • Clinical cure and failure followed appropriately was determined by need • Vancomycin dosing for further treatment in • Diagnosis of C. Difficile the opinion of the infection investigator• Blinding maintained by similar daily dosing schedule • Vancomycin treatment duration for 10 days vs. 14• Use of other potentially days effective treatments not permitted
  28. 28. Statistical Analysis Good Could Be Better• Non-inferiority margin • No mention of study power defined as -10 percentage goal or achievement points • Time to resolution of• Appropriate statistical diarrhea measured in hours, methods used to analyze while assessed daily primary and secondary outcomes
  29. 29. Results Good Could Be Better• Results of each identified study • Adherence was measured to outcome is addressed for both be similar but no mention as mITT and PP population and a to the method of adherence chart included testing• Subgroup analysis performed • Success of blinding not• Adverse effects were reported measured and well documented• No subjects discontinued the study due to intolerance or allergy to the study medication
  30. 30. Effect of Severity on Fidaxomicin• Clinical Cure Vancomycin seemed to show increased trend in clinical cure with increasing severity, while fidaxomicin seemed to show a decrease• P-Values were not given94% 92.2% 96% 94.9% 94.3% 91.9%92% 94%90% 92% 93.0%88% 88.6% 90%86% 85.0% 88% 88.1%84% 88.7% 83.0% 86%82% 82.1% 86.3%80% 84% Severity vs. Clinical Cure Severity vs. Clinical Cure Modified ITT Population Per-Protocol Population * Graphs generated from data found in Table 2.
  31. 31. Discussion and Conclusion Good Could Be Better• Primary and Secondary • No limitations are identified conclusions were valid and supported by the presented • Laboratory abnormalities data were of statistical significance, but not• Issue of the inability to reduce addressed the rate of recurrence with the resistant strain was addressed• Discussion is comprehensive and establishes study value
  32. 32. Overall Impression• Study was ethical, appropriately conducted, and produced useful results• Bias may be present, considering the conductors of data analysis were affiliated with the drug manufacturer• Non-inferiority of fidaxomicin to vancomycin was established• Confounders not considered • Origin of infection • H-2 antagonist and Proton Pump Inhibitor use• Need for a reassessment of fidaxomicin versus vancomycin in patients with severe Clostridium Difficile infection
  33. 33. Study Applications• This study aided in the FDA decision for approval of Fidaxomicin (Dificid®) in May 2011• Proving non-inferiority, fidaxomicin provides a reasonable alternative to vancomycin in the treatment of Clostridium Difficile associated diarrhea in the future• Currently being investigated are new indications for the drug and an oral suspension formulation
  34. 34. QUESTIONS?
  35. 35. References• Article Supplementary Appendix. New England Journal of Medicine Website. Available online at: http://www.nejm.org/doi/suppl/10.1056/NEJMoa0910812/suppl_file/nejmoa0910812 _appendix.pdf. Accessed: 6/10/11.• Aseeri M, Schroeder T, Kramer J, et al. “Gastric Acid Suppression by Proton-pump Inhibitors as a Risk Factor for Clostridium difficile- Associated Diarrhea in Hospitalized Patients”. Am J Gastroenterol. 2008;103: 2308-2313.• Cohen SH, Gerding DN, Johnson S, et al. “Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA)” Infect Control Hosp Epidemiol. 2010; 31(5): 000-000.• Louie TJ, Miller MA, Mullane KM, et al. “Fidaxomicin versus Vancomycin for Clostridium difficile Infection”. N Eng J Med. 2011; 364(5): 422-31.

×